MRTX1133 PHARMACEUTICAL COMPOSITIONS

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/543,834, filed, Oct. 12, 2023, the entire content of which is hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention generally relates to solid pharmaceutical compositions of MRTX1133 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1Hpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol); methods for preparing these compositions, and methods of their use for the treatment of various diseases and disorders.

BACKGROUND OF THE INVENTION

Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors regulating a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas. (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma. KRAS G12D mutation is present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non-small cell lung carcinoma patients and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8):818-831. Dataset Version 4).

The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy.

Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002/anie201201358) as well recent advances in the covalent targeting of an allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, especially KRas G12D.

A noncovalent inhibitor of KRas G12D is MRTX1133 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1Hpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol). An amorphous form of this compound was described in International Patent Application PCT/US2020/048194 filed Aug. 27, 2020 and published as WIPO publication WO2021/041671 on Mar. 4, 2021 at Example 252. The compound is also described in Qinheng Zheng et al, Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS^G12D Inhibitor, J. Med. Chem, 2022, 65, 4, 3123-3133.

A need therefore exists for a pharmaceutical composition of MRTX1133 which displays suitable bioavailability and shelf-life stability, which is not susceptible to liquid capsule leakage over time, and which has fewer side effects compared with capsule formulations.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a solid pharmaceutical composition, suitable for oral administration to a subject, including but not limited to a human subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical composition, after administration to the subject, is capable of providing AUC_0→∞ (the area under the curve of a plot of plasma drug concentration versus time) for MRTX1133 of at least, or about, 6900 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→last for MRTX1133 of at least, or about, 6700 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_24→48 for MRTX1133 of at least, or about, 3900 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→36 for MRTX1133 of at least, or about, 4700 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→24 for MRTX1133 of at least, or about, 2800 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→12 for MRTX1133 of at least, or about, 700 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing C_max for MRTX1133 of at least, or about, 710 ng/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing: a) AUC_0→∞ for MRTX1133 of at least, or about, 6900 ng*hr/mL; b) AUC_0→last for MRTX1133 of at least, or about, 6700 ng*hr/mL; c) AUC_24→48 for MRTX1133 of at least, or about, 3900 ng*hr/mL; d) AUC_0→36 for MRTX1133 of at least, or about, 4700 ng*hr/mL; e) AUC_0→24 for MRTX1133 of at least, or about, 2800 ng*hr/mL; f) AUC_0→12 for MRTX1133 of at least, or about, 700 ng*hr/mL; and g) C_max for MRTX1133 of at least, or about, 710 ng/mL.

In another embodiment, the solid pharmaceutical composition provides a T_max of between about 14 hours and about 22 hours.

In any of the embodiments, it is not required that the recited pharmacokinetic (PK) values, such as AUC_0→∞, AUC_0→last, AUC_24→48, AUC_0→36, AUC_0→24, AUC_0→12 and C_max, are achieved by administering a single pharmaceutical composition. The invention contemplates, and explicitly includes, embodiments where these PK values are achieved following administration of several capsule pharmaceutical compositions as a single dose (e.g., if a solid pharmaceutical composition comprises 150 mg MRTX1133, the single dose may include, for example, three of such pharmaceutical compositions, for the total administered amount of 450 mg MRTX1133).

In another embodiment, MRTX1133 is present as a salt thereof.

In another embodiment, the solid pharmaceutical composition comprises at least one additional anticancer compound in addition to MRTX1133.

In one embodiment, the solid pharmaceutical composition is in the form of a capsule.

In another embodiment, the solid pharmaceutical composition is in the form of a powder or a tablet, including an encapsulated powder.

In another embodiment, the solid pharmaceutical composition is in the form of a tablet.

In another embodiment, the tablet of the invention comprises a film coat.

In one embodiment, the pharmaceutical composition of the invention comprises MRTX1133 and sucrose acetate isobutyrate (“SAIB”).

In one embodiment, the capsule pharmaceutical composition of the invention comprises MRTX1133, SAIB, an antioxidant, a solvent, a surfactant, and an emulsifier.

In a preferred embodiment, an antioxidant comprises propyl gallate (PG).

In a preferred embodiment, the solvent comprises ethanol.

In a preferred embodiment, the surfactant is selected from the group consisting of polyoxylglycerides (e.g., caprylocaproyl Polyoxyl-8 glycerides), lauroyl polyoxyl-32 glycerides, and combinations thereof.

In a preferred embodiment, the emulsifier comprises D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS).

In another embodiment, the tablet of the invention comprises: MRTX1133, one or more diluents, a disintegrant, a glidant, a lubricant, and a film coat.

In a preferred embodiment, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, and combinations thereof.

In another preferred embodiment, the disintegrant comprises crospovidone.

In another preferred embodiment, the glidant comprises colloidal silicon dioxide.

In another preferred embodiment, the lubricant comprises magnesium stearate.

In a preferred embodiment, the tablet of the invention comprises MRTX1133, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate and a film coat.

In another embodiment, the solid pharmaceutical composition is provided as a unit dosage form.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 25 mg.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 50 mg.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 100 mg.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 150 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 200 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 300 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 400 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 600 mg.

In one embodiment, the tablets are extended release (ER) tablets.

In one embodiment, the amount of MRTX1133 in the composition is between 5-50%; preferably between 10-45%; more preferably between 15-40%, and most preferably between 20-40% by weight of the composition.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 constituting about 10-40% of the composition;
  • (2) SAIB constituting about 35-60% of the composition;
  • (3) an antioxidant constituting about 0-5% of the composition;
  • (4) a solvent constituting about 10% of the composition;
  • (5) an emulsifier constituting about 0-15% of the composition; and
  • (6) a surfactant constituting up to about 10-25% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In a preferred embodiment, MRTX1133 constitutes between about 10% and about 20% of the composition.

In another preferred embodiment, MRTX1133 constitutes about 15% of the composition.

In another preferred embodiment, MRTX1133 constitutes about 20% of the composition.

In another preferred embodiment, MRTX1133 constitutes about 35% of the composition.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 at about 20% of the composition;
  • (2) SAIB at about 35% of the composition;
  • (3) propyl gallate at about 5% of the composition;
  • (4) ethanol at about 10% of the composition;
  • (5) lauroyl polyoxyl-32 glycerides at about 5% of the composition;
  • (6) Vitamin E TPGS at about 10% of the composition; and
  • (7) Caprylocaproyl Polyoxyl-8 glycerides at about 15% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 at about 20% of the composition;
  • (2) SAIB at about 35% of the composition;
  • (3) propyl gallate at about 5% of the composition;
  • (4) ethanol at about 10% of the composition;
  • (5) lauroyl polyoxyl-32 glycerides at about 10% of the composition; and
  • (6) Vitamin E TPGS at about 20% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 at about 20% of the composition;
  • (2) SAIB at about 35% of the composition;
  • (3) propyl gallate at about 5% of the composition;
  • (4) ethanol at about 10% of the composition;
  • (5) Vitamin E TPGS at about 15% of the composition; and
  • (6) Caprylocaproyl Polyoxyl-8 glycerides at about 15% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 at about 20% of the composition;
  • (2) SAIB at about 35% of the composition;
  • (3) ethanol at about 10% of the composition;
  • (4) lauroyl polyoxyl-32 glycerides at about 5% of the composition;
  • (5) Vitamin E TPGS at about 15% of the composition; and
  • (6) Caprylocaproyl Polyoxyl-8 glycerides at about 15% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 at about 20% of the composition;
  • (2) SAIB at about 40% of the composition;
  • (3) propyl gallate at about 5% of the composition;
  • (4) ethanol at about 10% of the composition;
  • (5) lauroyl polyoxyl-32 glycerides at about 5% of the composition; and
  • (6) Caprylocaproyl Polyoxyl-8 glycerides at about 20% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In another embodiment, the composition is in the form of a tablet and comprises a film coat.

In another embodiment, the solid pharmaceutical composition is prepared by a process which comprises the steps of:

• • (a) mixing MRTX1133 and one or more solvents together to dissolve MRTX1133;
  • (b) adding an antioxidant, a surfactant and an emulsifier to the mixture of step (a) and stirring the mixture until all ingredients are dissolved;
  • (c) adding SAIB and a solvent to the mixture of step (b) and stirring until a uniform solution is formed;
  • (d) removing volatile solvents from the mixture of step (c); and
  • (e) encapsulating the solution of step (d) in capsules.

In one embodiment, the removal of volatile solvents in step (d) comprises reduced pressure evaporation.

In one embodiment, the solid pharmaceutical composition (e.g., a capsule or a tablet) may comprise additional excipients selected from the group consisting of diluents, fillers, super-disintegrants, binders, glidants, lubricants, and combinations thereof.

In another embodiment, the invention is directed to a method of treating cancer in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of the solid pharmaceutical composition of the present invention. In one embodiment, the therapeutically effective amount is at least, or about, 25 mg of MRTX1133. In another embodiment, the therapeutically effective amount is at least, or about, 50 mg of MRTX1133. In another embodiment, the therapeutically effective amount is at least, or about, 100 mg of MRTX1133. In one embodiment, the therapeutically effective amount is at least, or about, 150 mg of MRTX1133. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the KRas G12D-associated cancer is lung cancer. In one embodiment, the solid pharmaceutical composition is a capsule.

Also provided herein are methods for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of the solid pharmaceutical composition of the present invention. In one embodiment, the solid pharmaceutical composition is a capsule.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 contains pharmacokinetic (PK) profiles of the tested formulations.

FIG. 2 is a graph of plasma concentration of MRTX1133 after MRTA191 dosing.

FIG. 3 is a graph of plasma concentration of MRTX1133 after MRTA193 dosing.

FIG. 4 is a graph of plasma concentration of MRTX1133 after MRTA194 dosing.

FIG. 5 is a graph of plasma concentration of MRTX1133 after MRTA195 dosing.

FIG. 6 is a graph of plasma concentration of MRTX1133 after MRTA196 dosing.

FIG. 7 is a graph of plasma concentration of MRTX1133 after MRTA197 dosing.

FIG. 8 is a graph of plasma concentration of MRTX1133 after MRTA132 dosing.

FIG. 9 is a graph of single-dose pharmacokinetic profiles of the evaluated doses of MRTX133 in humans.

FIG. 10 is a graph of single-dose pharmacokinetic profiles of the evaluated doses of MRTX133 in humans.

FIG. 11 shows single-dose and multiple dose pharmacokinetic profiles of the evaluated doses of MRTX133 in humans.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “MRTX1133” as used herein refers to a compound with the following formula:

as well as pharmaceutically acceptable salts of this compound. The compound has the following chemical name: (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1Hpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol). The invention encompasses amorphous and crystalline forms of MRTX1133. An amorphous form of this compound was described in International Patent Application PCT/US2020/048194 filed Aug. 27, 2020 and published as WIPO publication WO2021/041671 on Mar. 4, 2021 at Example 252. The compound is also described in Qinheng Zheng et al, Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS^G12D Inhibitor, J. Med. Chem, 2022, 65, 4, 3123-3133. The contents of this patent application and of the literature reference are hereby incorporated by reference in their entirety.

As used herein, “KRas G12D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Asp.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term “solid composition” as used herein is intended to encompass capsules (including but not limited to gelatinous capsules containing viscous solution), tablets, powders, and other non-liquid formulations.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

The term “crystalline” and related terms used herein, when used to describe a substance, component or product, means that the substance, component or product is crystalline as determined by X-ray diffraction. See, for example, Remington's Pharmaceutical Sciences, 18^th ed., Mack Publishing, Easton PA, p. 173 (1990); The United States Pharmacopeia, 23^rd ed., pp. 1843-1844 (1995); the contents of which are hereby incorporated by reference in their entireties.

The term “crystalline forms” and related terms herein refers to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof.

The term “pharmaceutically acceptable salts” is meant to include salts of active compounds which are prepared with relatively nontoxic acids. Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic; propionic; isobutyric; maleic; malonic; benzoic; succinic; suberic; fumaric; mandelic; phthalic; benzenesulfonic; toluenesulfonic, including p-toluenesulfonic, m-toluenesulfonic, and o-toluenesulfonic; citric; tartaric; methanesulfonic; and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al. J. Pharm. Sci. 66:1-19 (1977)).

The term, “amorphous form,” as used herein, refers to a noncrystalline form of a substance.

The terms, “polymorphs” and “polymorphic forms” and related terms herein refer to crystal forms of a molecule. Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in bioavailability). Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation.

Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., IR and Raman spectroscopy, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.

The term, “solvate,” as used herein, refers to a crystal form of a substance which contains solvent. The term “hydrate” refers to a solvate wherein the solvent is water.

The term, “desolvated solvate,” as used herein, refers to a crystal form of a substance which can only be made by removing the solvent from a solvate.

The term “excipient” refers to an inactive ingredient of the pharmaceutical compositions of the invention. It includes, but is not limited to, solvents, wetting agents, diluents, superdisintegrants, binders, glidants, and lubricants.

The terms “treat”, “treating” or “treatment”, as used herein, refer to the reduction or amelioration of the progression, severity, and/or duration of a disorder or the eradication, reduction or amelioration of symptoms of a disorder, or the delay of the recurrence or onset of a disorder or one or more symptoms thereof in a subject that results from the administration of one or more compound.

As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.

As used herein, the term “subject,” “individual,” or “patient,” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12D mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12D mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12D mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12D mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12D gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12D mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

The term “pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman R E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery M D, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has KRas G12D mutation using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12D-associated cancer, a patient having one or more symptoms of a KRas G12D-associated cancer, and/or a patient that has an increased risk of developing a KRas G12D-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.

The term “regulatory agency” is a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

As used herein, a “therapeutically effective amount” is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12D. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

As used herein, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The term, “AUC,” as used herein, refers to the area under the curve of a plot of plasma drug concentration versus time.

The term, “T_max,” as used herein, refers to the time after administration of a drug when the maximum plasma concentration is reached.

A “KRas G12D-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.

DETAILED DESCRIPTION OF COMPOSITIONS AND METHODS

The present invention is based on a surprising discovery that solid pharmaceutical compositions (e.g., capsules) comprising MRTX1133 and that also include SAIB (sucrose acetate isobutyrate) result in superior absorption of MRTX1133 as compared with pharmaceutical compositions that comprise MRTX1133 but do not comprise SAIB.

In one embodiment, the present invention provides a solid pharmaceutical composition, suitable for oral administration to a subject, including but not limited to a human subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical composition, after administration to the subject, is capable of providing AUC_0→∞ (the area under the curve of a plot of plasma drug concentration versus time) for MRTX1133 of at least, or about, 6900 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→last for MRTX1133 of at least, or about, 6700 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_24→48 for MRTX1133 of at least, or about, 3900 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→36 for MRTX1133 of at least, or about, 4700 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→24 for MRTX1133 of at least, or about, 2800 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing AUC_0→12 for MRTX1133 of at least, or about, 700 ng*hr/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing C_max for MRTX1133 of at least, or about, 710 ng/mL.

In another embodiment, the solid pharmaceutical composition, after administration to a subject, is capable of providing: a) AUC_0→∞ for MRTX1133 of at least, or about, 6900 ng*hr/mL; b) AUC_0→last for MRTX1133 of at least, or about, 6700 ng*hr/mL; c) AUC_24→48 for MRTX1133 of at least, or about, 3900 ng*hr/mL; d) AUC_0→36 for MRTX1133 of at least, or about, 4700 ng*hr/mL; e) AUC_0→24 for MRTX1133 of at least, or about, 2800 ng*hr/mL; f) AUC_0→12 for MRTX1133 of at least, or about, 700 ng*hr/mL; and g) C_max for MRTX1133 of at least, or about, 710 ng/mL.

In another embodiment, the solid pharmaceutical composition provides a T_max of between about 14 hours and about 22 hours.

In any of the embodiments, it is not required that the recited pharmacokinetic (PK) values, such as AUC_0→∞, AUC_0→last, AUC_24→48, AUC_0→36, AUC_0→24, AUC_0→12 and C_max, are achieved by administering a single pharmaceutical composition. The invention contemplates, and explicitly includes, embodiments where these PK values are achieved following administration of several capsule pharmaceutical compositions as a single dose (e.g., if a solid pharmaceutical composition comprises 150 mg MRTX1133, the single dose may include, for example, three of such pharmaceutical compositions, for the total administered amount of 450 mg MRTX1133).

In another embodiment, MRTX1133 is present as a salt thereof.

In another embodiment, the solid pharmaceutical composition comprises at least one additional anticancer compound in addition to MRTX1133.

In one embodiment, the solid pharmaceutical composition is in the form of a capsule.

In another embodiment, the solid pharmaceutical composition is in the form of a powder or a tablet, including an encapsulated powder.

In another embodiment, the solid pharmaceutical composition is in the form of a tablet.

In another embodiment, the tablet of the invention comprises a film coat.

In one embodiment, the pharmaceutical composition of the invention comprises MRTX1133 and sucrose acetate isobutyrate (“SAIB”).

In one embodiment, the capsule pharmaceutical composition of the invention comprises MRTX1133, SAIB, an antioxidant, a solvent, a surfactant, and an emulsifier.

In a preferred embodiment, an antioxidant comprises propyl gallate (PG).

In a preferred embodiment, the solvent comprises ethanol.

In a preferred embodiment, the surfactant is selected from the group consisting of polyoxylglycerides, lauroyl polyoxyl-32 glycerides, and combinations thereof.

In a preferred embodiment, the emulsifier comprises D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS).

In another embodiment, the tablet of the invention comprises: MRTX1133, one or more diluents, a disintegrant, a glidant, a lubricant, and a film coat.

In a preferred embodiment, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, and combinations thereof.

In another preferred embodiment, the disintegrant comprises crospovidone.

In another preferred embodiment, the glidant comprises colloidal silicon dioxide.

In another preferred embodiment, the lubricant comprises magnesium stearate.

In a preferred embodiment, the tablet of the invention comprises MRTX1133, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate and a film coat.

In another embodiment, the solid pharmaceutical composition is provided as a unit dosage form.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 25 mg.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 50 mg.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 100 mg.

In one embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 150 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 200 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 300 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 400 mg.

In another embodiment, the amount of MRTX1133 in the solid pharmaceutical composition is at least, or about, 600 mg.

In one embodiment, the tablets are extended release (ER) tablets.

In one embodiment, the amount of MRTX1133 in the composition is between 5-50%; preferably between 10-45%; more preferably between 15-40%, and most preferably between 20-40% by weight of the composition.

In another embodiment, the composition is in the form of a capsule and comprises:

• • (1) MRTX1133 constituting about 10-40% of the composition;
  • (2) SAIB constituting about 35-60% of the composition;
  • (3) an antioxidant constituting about 0-5% of the composition;
  • (4) a solvent constituting about 10% of the composition;
  • (5) an emulsifier constituting about 0-15% of the composition; and
  • (6) a surfactant constituting up to about 10-25% of the composition;
    wherein all percentages are percentages by weight and wherein the total weight is 100%.

In a preferred embodiment, MRTX1133 constitutes between about 10% and about 20% of the composition.

In another preferred embodiment, MRTX1133 constitutes about 15% of the composition.

In another preferred embodiment, MRTX1133 constitutes about 20% of the composition.

In another preferred embodiment, MRTX1133 constitutes about 35% of the composition.

In another embodiment, the composition is in the form of a tablet and comprises a film coat.

In another embodiment, the solid pharmaceutical composition is prepared by a process which comprises the steps of:

• • (a) mixing MRTX1133 and one or more solvents together to dissolve MRTX1133;
  • (b) adding an antioxidant, a surfactant and an emulsifier to the mixture of step (a) and stirring the mixture until all ingredients are dissolved;
  • (c) adding SAIB and a solvent to the mixture of step (b) and stirring until a uniform solution is formed;
  • (d) removing volatile solvents from the mixture of step (c); and
  • (e) encapsulating the solution of step (d) in capsules.

In one embodiment, the removal of volatile solvents in step (d) comprises reduced pressure evaporation.

In one embodiment, the solid pharmaceutical composition (e.g., a capsule or a tablet) may comprise additional excipients selected from the group consisting of diluents, fillers, super-disintegrants, binders, glidants, lubricants, and combinations thereof.

Also provided herein are methods for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of the solid pharmaceutical composition of the present invention. In one embodiment, the solid pharmaceutical composition is a capsule.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including, for example, the activity of the specific polymorph employed, the metabolic stability and length of action of that polymorph, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, and the severity of the patient's condition.

The pharmaceutical compositions provided herein can be combined with other compounds having related utilities to treat or prevent cancer. In many instances, administration of the subject pharmaceutical compositions in conjunction with these alternative agents enhances the efficacy of such agents. Accordingly, in some instances, the present pharmaceutical compositions, when combined or administered in combination with, e.g., anticancer agents, can be used in dosages which are less than the expected amounts when used alone, or less than the calculated amounts for combination therapy.

EXAMPLES OF THE INVENTION

The following Examples illustrate the invention.

Example 1: MRTX1133 Formulations

This example illustrates MRTX1133 solid pharmaceutical compositions.

Materials and Methods

Undenatured, 200 proof, Ethyl Alcohol and Dichloromethane (DCM), HPLC grade, were purchased from Sigma Aldrich; Propyl Gallate NF was purchased from Spectrum Chemicals; Vitamin E TPGS was purchased from Antares Pharma; Gelucire® 44/14 (Lauroyl Polyoxyl-32 glycerides) and Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) were provided by Gattefosse; Sucrose Acetate Isobutyrate (SAIB), BioSustane SAIB NF, was purchased from Eastman Chemicals; MRTX1133 (96%) was provided by Mirati Therapeutics Process Chemistry Group.

Instruments: Agilent 1260 HPLC equipped with a reverse phase column and method and Agilent Gas Chromatograph model. Reduced pressure evaporation equipment: Heidolph model Hei-VAP Core.

Table 1 illustrates the tested compositions.

TABLE 1
Drug Product, Unit Composition

% Content

Ingredient	MRTA132	MRTA191	MRTA193	MRTA194	MRTA195	MRTA196	MRTA197

MRTX1133	10	20	20	20	20	20	20
Propyl Gallate	0	5	5	5	0	5	5
Ethanol	5	10	10	10	10	10	10
Gelucire ® 44/14	5	5	10	0	5	10	5
Vitamin E TPGS	10	10	20	15	15	25	0
Labrasol ® ALF	15	15	0	15	15	30	20
SAIB	55	35	35	35	35	0	40
Total	100	100	100	100	100	100	100

Preparation of MRTA132

5.50 grams of MRTX1133 were mixed by magnetic stirring with 62.2 g Ethanol to completely dissolve and form a dark reddish-brown solution. To this solution, Gelucire® 44/14, 2.47 g; Vitamin E TPGS, 5.06 g; and Labrasol® ALF, 7.53 g were added followed by stirring until all material dissolved and a reddish-brown solution was formed. To this solution, 29.5 g of previously prepared SAIB:Ethanol (9:1) solution, was added under stirring (29.5 g delivered 26.55 g of SAIB). The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvent under reduced pressure evaporation afforded the following solvent level: Ethanol, 6.58%.

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 700 mg formulation (targeted MRTX1133 strength: 70 mg).

MRTX1133 strength and purity were determined by HPLC; strength: 113.2 mg MRTX1133/g formulation and purity by HPLC was 99.61%.

Preparation of MRTA191

27.08 grams of MRTX1133 were mixed by magnetic stirring with 81.2 g Ethanol and 54.00 g DCM to completely dissolve and form a dark reddish-brown solution. To this solution, propyl gallate, 6.43 g; Gelucire® 44/14, 6.43 g; Vitamin E TPGS, 12.89 g; and Labrasol® ALF, 19.28 g were added followed by stirring until all material dissolved and a reddish-brown solution was formed. To this solution, 52.32 g of previously prepared SAIB:Ethanol (9:1) solution, was added under stirring (52.32 g delivered 47.09 g of SAIB). The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: Ethanol, 10.19%; DCM, 412 ppm.

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 750 mg formulation (targeted MRTX1133 strength: 150 mg).

MRTX1133 strength and purity were determined by HPLC; strength: 189.8 mg MRTX1133/g formulation and purity by HPLC was 97.85%.

Preparation of MRTA193

9.57 grams of MRTX1133 were mixed by magnetic stirring with 26.82 g Ethanol and 17.84 g DCM to completely dissolve and form a dark reddish-brown solution. To this solution, propyl gallate, 2.23 g; Gelucire® 44/14, 2.28 g; Vitamin E TPGS, 10.15 g were added followed by stirring until all material dissolved and a reddish-brown solution was formed. To this solution, 19.85 g of previously prepared SAIB:Ethanol (9:1) solution, was added under stirring (19.84 g delivered 17.86 g of SAIB). The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: Ethanol, 9.23%; DCM, 281 ppm.

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 750 mg formulation and 150 mg MRTX1133.

MRTX1133 strength and purity were determined by HPLC; strength: 190.7 mg MRTX1133/g MRTA193 formulation and purity by HPLC was 98.12%.

Preparation of MRTA194

10.0 grams of MRTX1133 were mixed by magnetic stirring with 30.00 g Ethanol and 20.00 g DCM to completely dissolve and form a dark reddish-brown solution.

To this MRTX1133 solution, propyl gallate, 2.50 g; Vitamin E TPGS, 7.50 g; and Labrasol® ALF, 7.50 g were added followed by mixing under magnetic stirring until all solid material dissolved and a uniform dark reddish-brown solution was formed. To this solution 19.45 g, SAIB:Ethanol (9:1) solution was added under stirring (19.45 g delivered 17.50 g of SAIB). The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: Ethanol, 8.66%; DCM, 544 ppm.

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 750 mg formulation and 150 mg MRTX1133.

MRTX1133 strength and purity were determined by HPLC; strength: 199 mg MRTX1133/g MRTA194 formulation and purity by HPLC was 98.54%.

Preparation MRTA195

8.93 grams of MRTX1133 were mixed by magnetic stirring with 26.80 g Ethanol and 17.90 g DCM to completely dissolve and form a dark reddish-brown solution.

To this MRTX1133 solution, Gelucire® 44/14, 2.23 g; Vitamin E TPGS, 6.70 g; and Labrasol® ALF, 6.70 g were added followed by mixing under magnetic stirring until all solid material dissolved and a uniform dark reddish-brown solution was formed. To this solution 17.36 g, SAIB:Ethanol (9:1) solution was added under stirring (17.36 g delivered 15.63 g of SAIB). The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: Ethanol, 8.00%; DCM, 507 ppm.

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 750 mg formulation and 150 mg MRTX1133.

MRTX1133 strength and purity were determined by HPLC; strength: 200.2 mg MRTX1133/g MRTA195 formulation and purity by HPLC was 98.35%.

Preparation of MRTA196

8.93 grams of MRTX1133 was mixed by magnetic stirring with 28.48 g Ethanol and 19.02 g DCM to completely dissolve and form a dark reddish-brown solution.

To this MRTX1133 solution, propyl gallate, 2.22 g; Gelucire® 44/14, 4.50 g; Vitamin E TPGS, 11.18 g; and Labrasol® ALF, 13.50 g were added followed by mixing under magnetic stirring until all solid material dissolved and a uniform dark reddish-brown solution was formed. The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: DCM<600 ppm and ethanol 9-12% both determined by Gas Chromatography; (ethanol, 6.59%; DCM, 978 ppm).

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: Ethanol, 6.59%; DCM, 9.78 ppm.

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 750 mg formulation (targeted MRTX1133 strength: 150 mg).

MRTX1133 strength and purity were determined by HPLC; strength (201.1 mg MRTX1133 per g MRTA196 formulation) and purity by HPLC was (98.46%).

Preparation of MRTA197

9.00 grams of MRTX1133 were mixed by magnetic stirring with 27.01 g Ethanol and 18.03 g DCM to completely dissolve and form a dark reddish-brown solution.

To this MRTX1133 solution, propyl gallate, 2.28 g; Gelucire® 44/14, 2.25 g; and Labrasol® ALF, 9.01 g were added followed by mixing under magnetic stirring until all solid material dissolved and a uniform dark reddish-brown solution was formed.

To this solution, 20.01 g of previously prepared SAIB:Ethanol (9:1) solution, was added under stirring (20.01 g delivered 18.00 g of SAIB). The solution was allowed to stir for at least 15-30 mins or, until a uniform, slightly viscous solution was formed.

Removal of volatile solvents under reduced pressure evaporation afforded the following solvent levels: Ethanol, 10.02%; DCM, not detectable (ND).

The resulting viscous solution was encapsulated in gelatin size 00 capsules containing approximately 750 mg formulation and 150 mg MRTX1133.

MRTX1133 strength and purity were determined by HPLC; strength: 267.01 mg MRTX1133/g MRTA197 formulation and purity by HPLC was 98.08%.

Example 2: Pharmacokinetics in Dogs

Test System and Study Design

Three, non-naïve, fasted and pentagastrin-pretreated (IM injection, 6 μg/kg, 30 mins prior to each administration), male beagle dogs (≥8 kg and ≥6 months old) were administered 3 (three) 150 mg MRTX1133 (00 size) capsules, administered at T=0, 12, 24, 36 hours for a total of 6 capsules per day.

Blood Samples were Collected on:

• • T=0, 0.25, 0.5, 1, 2, 4, 8, 12, 13, 14, 15, 18, 24, 25, 26, 27, 30, 36, 37, 38, 39, 42 and 48 h.

Blood was collected into commercially available tubes (Jiangsu Kangjian Medical Supplies co., LTD) containing Potassium (K₂) EDTA (0.85-1.15 mg) gently inverted several times to ensure mixing and placed on wet ice until processed for plasma. Samples were centrifuged (3,200×g for 10 minutes at 2 to 8° C.) within 30 minutes from collection. The plasma sample (2*100 μL, one for analysis, one for backup) were transferred into labeled polypropylene micro-centrifuge tubes and stored frozen in a ≤−60° C. freezer until analyzed.

Test articles concentrations (ng/mL) in plasma were quantified by LC-MS/MS with internal standard.

Results

Table 2 shows results of a bioavailability study of the tested compositions.

TABLE 2
Analysis of MRTX1133 Primary Pharmacokinetic Endpoints

	MRTA191	MRTA193	MRTA194	MRTA195	MRTA196	MRTA197
Parameter	n = 3*	n = 3*	n = 3*	n = 3*	n = 3*	n = 3*

Cmax (ng/mL)	955	833	724	1012	388	638
Tmax (h)	21.7	22.0	14.3	17.5	9.00	13.2
T1/2 (h)	2.81	3.51	3.00	4.07	8.54	4.17
Tlast (h)	48.0	48.0	48.0	48.0	48.0	48.0
AUC0-12(h · ng/mL)	1128	716	727	1033	567	1238
AUC0-24(h · ng/mL)	3587	3198	2836	3119	1543	3829
AUC0-36(h · ng/mL)	6908	6849	4777	5416	3042	6950
AUC24-48(h · ng/mL)	5538	6030	3951	4720	2609	5384
AUC0-last (ng · h/mL)	9125	9228	6787	7839	4152	9213
AUC0-inf (ng · h/mL)	9320	9505	6988	8261	4888	9619
MRT0-last (h)	25.3	26.1	25.3	25.3	25.7	25.0
MRT0-inf (h)	25.8	26.9	26.0	26.8	32.6	26.1
AUCExtra (%)	2.13	2.89	2.89	5.20	14.7	3.95
AUMCExtra (%)	4.30	5.71	5.81	10.8	24.8	8.17
AUC0-12 = area under the plasma concentration time curve from time 0 to 12 h;
AUC0-24 = area under the plasma concentration time curve from time 0 to 24 h;
AUC0-36 = area under the plasma concentration time curve from time 0 to 36 h;
AUC24-48 = area under the plasma concentration time curve from time 24 to 48 h;
AUC0-last = area under the plasma concentration time curve from time 0 to 48 h or the time of the last sample draw;
AUC0-inf area under the plasma concentration time curve from time zero to infinity;
MRT0-last mean residence time from 0 to the time of the last sample draw;
MRT0-inf mean residence time from 0 to infinity;
AUCExtra means a fraction of the total AUC that is due to the extrapolated AUC;
AUMCExtra means a fraction of the total AUMC that is due to the extrapolated AUMC, wherein AUMC is the area under the moment curve

Pharmacokinetic studies in beagle dogs were designed to administer 450 mg dose twice daily for two days. From the results of the study, it is evident that the first 24 hours of administration, blood levels demonstrated the need for MRTX1133 equilibration; thus, only the second 24 hours are taken into consideration to assess success.

The pharmacokinetic profiles of the tested formulations are shown in FIG. 1. The X-axis is time (hours) and the Y-axis is blood concentration (ng/mL). The main measure of success of each formulation is the ability to deliver MRTX1133 in blood at levels above 100 ng/mL during the 12 hours post-administration time interval. Based on the data illustrated in FIG. 1, formulations MRTA191, MRTA193, MRTA194, MRTA195, MRTA197 show rather similar pharmacokinetic characteristics, delivering 100 ng/mL MRTX1133 for the majority of time post dosage administration. Formulation MRTA196, does not contain SAIB and absorption above the 100 ng/mL in Beagle dogs was not as desirable as formulations MRTA191, MRTA193, MRTA194, MRTA195 and MRTA197. Although for MRTA196 for short periods, 100 ng/mL blood concentration is reached, the majority of post administration time, blood concentration remains below the desirable level.

Based on the pharmacokinetic data presented in this study, it was surprisingly found that SAIB plays an important role in the absorption of MRTX1133 in comparison with all other ingredients used.

Table 3 lists pharmacokinetic data of MRTA191 formulation. FIG. 2 is a graph of plasma concentration of MRTX1133 after MRTA191 dosing.

TABLE 3
Summary of MRTA191 Pharmacokinetic Parameters
MRTA191

	D1001	D1002	D1003	Mean		SD	CV (%)

Time (h)
0	BQL	BQL	BQL	ND	±	ND	ND
0.25	87.4	272	135	165	±	95.8	58.2
0.5	215	470	463	383	±	145	38.0
1	527	90.6	181	266	±	230	86.5
2	668	24.2	47.4	247	±	365	148
4	212	17.0	36.8	88.6	±	107	121
8	49.1	5.64	6.87	20.5	±	24.7	120
12	30.9	3.82	4.59	13.1	±	15.4	118
13	329	384	349	354	±	27.8	7.86
14	1290	624	495	803	±	427	53.1
15	464	210	192	289	±	152	52.7
18	267	59.0	48.0	125	±	123	99.0
24	86.0	38.4	62.2	62.2	±	23.8	38.3
25	1440	270	250	653	±	681	104
26	673	520	801	665	±	141	21.2
27	438	567	700	568	±	131	23.1
30	198	176	212	195	±	18.1	9.29
36	72.1	52.7	49.7	58.2	±	12.2	20.9
37	91.3	81.0	88.5	86.9	±	5.33	6.13
38	487	523	366	459	±	82.2	17.9
39	579	386	511	492	±	97.9	19.9
42	216	181	95.4	164	±	62.0	37.8
48	63.6	42.8	37.0	47.8	±	14.0	29.3
PK Parameters
Rsq_adj	0.967	1.00	0.848	—	±	—	—
No. points used for T1/2	3.00	3.00	4.00	ND	±	—	—
Cmax (ng/mL)	1440	624	801	955	±	429	44.9
Tmax (h)	25.0	14.0	26.0	21.7	±	6.66	30.7
T1/2 (h)	2.89	2.84	2.70	2.81	±	0.0985	3.50
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12(h · ng/mL)	2394	430	561	1128	±	1098	97.3
AUC0-24(h · ng/mL)	6416	2152	2194	3587	±	2450	68.3
AUC0-36(h · ng/mL)	10389	4812	5522	6908	±	3036	43.9
AUC24-48(h · ng/mL)	6675	4800	5138	5538	±	999	18.0
AUC0-last (ng · h/mL)	13091	6953	7332	9125	±	3440	37.7
AUC0-inf (ng · h/mL)	13356	7128	7476	9320	±	3500	37.5
MRT0-last (h)	22.2	27.3	26.3	25.3	±	2.70	10.7
MRT0-inf (h)	22.8	27.9	26.8	25.8	±	2.68	10.4
AUCExtra (%)	1.99	2.46	1.93	2.13	±	0.290	13.6
AUMCExtra (%)	4.55	4.61	3.73	4.30	±	0.492	11.4

Table 4 lists pharmacokinetic data of MRTA193 formulation. FIG. 3 is a graph of plasma concentration of MRTX1133 after MRTA193 dosing.

TABLE 4
Summary of MRTA193 Pharmacokinetic Parameters
MRTA193

	D1001	D1002	D1003	Mean		SD	CV (%)

Time (h)
0	BQL	BQL	BQL	ND	±	ND	ND
0.25	BQL	57.7	21.5	39.6	±	ND	ND
0.5	83.6	327	341	251	±	145	57.8
1	42.5	183	126	117	±	70.7	60.3
2	17.5	109	623	250	±	326	131
4	3.56	16.8	74.9	31.8	±	37.9	120
8	1.56	8.48	20.1	10.0	±	9.37	93.3
12	1.11	6.82	13.0	6.98	±	5.95	85.2
13	453	8.75	76.5	179	±	239	133
14	529	381	424	445	±	76.1	17.1
15	234	1060	542	612	±	417	68.2
18	147	190	133	157	±	29.7	19.0
24	30.7	52.2	29.5	37.5	±	12.8	34.1
25	213	887	777	626	±	362	57.8
26	495	825	409	576	±	220	38.1
27	377	733	451	520	±	188	36.1
30	182	590	147	306	±	246	80.4
36	44.3	97.9	130	90.7	±	43.3	47.7
37	136	165	909	403	±	438	109
38	411	372	455	413	±	41.5	10.1
39	397	635	168	400	±	234	58.4
42	100	280	85.3	155	±	108	69.9
48	44.1	86.5	38.8	56.5	±	26.1	46.3
PK Parameters
Rsq_adj	0.886	0.985	0.957	—	±	—	—
No. points used for T1/2	4.00	3.00	3.00	ND	±	—	—
Cmax (ng/mL)	529	1060	909	833	±	274	32.9
Tmax (h)	14.0	15.0	37.0	22.0	±	13.0	59.1
T1/2 (h)	2.96	3.18	4.38	3.51	±	0.764	21.8
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12 (ng · h/mL)	119	536	1493	716	±	705	98.4
AUC0-24 (ng · h/mL)	2206	3617	3771	3198	±	863	27.0
AUC0-36 (ng · h/mL)	4456	9166	6926	6849	±	2356	34.4
AUC24-48 (ng · h/mL)	4040	8713	5338	6030	±	2412	40.0
AUC0-last (ng · h/mL)	6246	12330	9109	9228	±	3044	33.0
AUC0-inf (ng · h/mL)	6434	12727	9354	9505	±	3149	33.1
MRT0-last (h)	27.1	27.6	23.5	26.1	±	2.24	8.58
MRT0-inf (h)	27.9	28.4	24.3	26.9	±	2.24	8.33
AUCExtra (%)	2.93	3.12	2.62	2.89	±	0.252	8.73
AUMCExtra (%)	5.50	5.78	5.85	5.71	±	0.185	3.24

Table 5 lists pharmacokinetic data of MRTA194 formulation. FIG. 4 is a graph of plasma concentration of MRTX1133 after MRTA194 dosing.

TABLE 5
Summary of MRTA194 Pharmacokinetic Parameters
MRTA194

	D2001	D2002	D2003	Mean		SD	CV (%)

Time (h)
0	BQL	BQL	BQL	ND	±	ND	ND
0.25	101	37.8	75.8	71.5	±	31.8	44.5
0.5	278	703	458	480	±	213	44.5
1	153	628	184	322	±	266	82.6
2	77.4	73.9	112	87.8	±	21.1	24.0
4	16.6	48.8	29.9	31.8	±	16.2	50.9
8	7.77	12.9	11.8	10.8	±	2.70	25.0
12	6.77	10.6	9.72	9.03	±	2.01	22.2
13	157	266	141	188	±	68.0	36.2
14	338	1030	622	663	±	348	52.4
15	519	325	183	342	±	169	49.3
18	165	133	104	134	±	30.5	22.8
24	45.0	37.1	30.6	37.6	±	7.21	19.2
25	415	414	340	390	±	43.0	11.0
26	358	242	301	300	±	58.0	19.3
27	161	280	302	248	±	75.9	30.6
30	88.6	276	141	169	±	96.7	57.4
36	40.7	59.6	41.4	47.2	±	10.7	22.7
37	185	275	121	194	±	77.4	39.9
38	425	970	486	627	±	299	47.6
39	333	429	352	371	±	50.8	13.7
42	74.4	128	110	104	±	27.3	26.2
48	46.9	53.6	37.4	46.0	±	8.14	17.7
PK Parameters
Rsq_adj	0.770	0.843	0.946	—	±	—	—
No. points used for T1/2	4.00	3.00	4.00	ND	±	—	—
Cmax (ng/mL)	519	1030	622	724	±	270	37.3
Tmax (h)	15.0	14.0	14.0	14.3	±	0.577	4.03
T1/2 (h)	3.11	3.17	2.71	3.00	±	0.250	8.34
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12(h · ng/mL)	455	1074	653	727	±	316	43.5
AUC0-24(h · ng/mL)	2694	3567	2248	2836	±	671	23.7
AUC0-36(h · ng/mL)	4226	5985	4120	4777	±	1048	21.9
AUC24-48(h · ng/mL)	3168	5033	3652	3951	±	968	24.5
AUC0-last (ng · h/mL)	5862	8600	5900	6787	±	1570	23.1
AUC0-inf (ng · h/mL)	6072	8845	6047	6988	±	1608	23.0
MRT0-last (h)	25.0	25.1	25.7	25.3	±	0.379	1.50
MRT0-inf (h)	25.9	25.8	26.4	26.0	±	0.321	1.23
AUCExtra (%)	3.47	2.77	2.42	2.89	±	0.535	18.5
AUMCExtra (%)	7.01	5.64	4.77	5.81	±	1.13	19.4

Table 6 lists pharmacokinetic data of MRTA195 formulation. FIG. 5 is a graph of plasma concentration of MRTX1133 after MRTA195 dosing.

TABLE 6
Summary of MRTA195 Pharmacokinetic Parameters
MRTA195

	D2001	D2002	D2003	Mean		SD	CV (%)

Time (h)
0	BQL	BQL	BQL	ND	±	ND	ND
0.25	196	126	94.9	139	±	51.8	37.3
0.5	1290	379	435	701	±	511	72.8
1	371	580	127	359	±	227	63.1
2	76.5	333	20.2	143	±	167	116
4	20.4	162	6.19	62.9	±	86.1	137
8	12.4	37.2	4.03	17.9	±	17.2	96.5
12	9.18	22.2	3.41	11.6	±	9.63	83.0
13	430	48.4	105	194	±	206	106
14	698	764	202	555	±	307	55.4
15	201	482	757	480	±	278	57.9
18	110	73.1	98.9	94.0	±	18.9	20.1
24	57.5	58.3	22.3	46.0	±	20.6	44.7
25	593	575	143	437	±	255	58.3
26	287	282	653	407	±	213	52.2
27	309	204	369	294	±	83.5	28.4
30	339	57.5	136	178	±	145	81.8
36	107	37.6	46.5	63.7	±	37.8	59.3
37	215	989	40.9	415	±	505	122
38	806	253	682	580	±	290	50.0
39	484	175	490	383	±	180	47.0
42	250	72.4	94.9	139	±	96.7	69.5
48	67.7	71.5	77.0	72.1	±	4.68	6.49
PK Parameters
Rsq_adj	1.00	0.549	0.656	—	±	—	—
No. points used for T1/2	3.00	4.00	4.00	ND	±	—	—
Cmax (ng/mL)	1290	989	757	1012	±	267	26.4
Tmax (h)	0.500	37.0	15.0	17.5	±	18.4	105
T1/2 (h)	3.17	5.85	3.19	4.07	±	1.54	37.9
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12 (ng · h/mL)	958	1787	354	1033	±	720	69.7
AUC0-24 (ng · h/mL)	2958	4079	2320	3119	±	890	28.6
AUC0-36 (ng · h/mL)	6085	5744	4419	5416	±	880	16.3
AUC24-48 (ng · h/mL)	6261	3711	4187	4720	±	1356	28.7
AUC0-last (ng · h/mL)	9219	7790	6507	7839	±	1357	17.3
AUC0-inf (ng · h/mL)	9528	8393	6861	8261	±	1338	16.2
MRT0-last (h)	27.3	21.5	27.1	25.3	±	3.29	13.0
MRT0-inf (h)	28.1	24.0	28.4	26.8	±	2.46	9.16
AUCExtra (%)	3.25	7.19	5.16	5.20	±	1.97	37.9
AUMCExtra (%)	6.08	16.9	9.56	10.8	±	5.52	50.9

Table 7 lists pharmacokinetic data of MRTA196 formulation. FIG. 6 is a graph of plasma concentration of MRTX1133 after MRTA196 dosing.

TABLE 7
Summary of MRTA196 Pharmacokinetic Parameters
MRTA196

	D1001	D1002	D1003	Mean		SD	CV (%)

Time (h)
0	BQL	BQL	BQL	ND	±	ND	ND
0.25	60.6	42.5	60.1	54.4	±	10.3	18.9
0.5	320	334	273	309	±	32.0	10.3
1	141	402	256	266	±	131	49.1
2	77.8	119	60.4	85.7	±	30.1	35.1
4	16.8	18.1	58.3	31.1	±	23.6	75.9
8	6.94	8.84	8.04	7.94	±	0.954	12.0
12	4.18	6.17	6.41	5.59	±	1.22	21.9
13	21.6	91.9	15.8	43.1	±	42.4	98.3
14	143	205	29.6	126	±	88.9	70.7
15	273	221	63.7	186	±	109	58.6
18	88.3	104	132	108	±	22.1	20.5
24	14.5	17.5	11.6	14.5	±	2.95	20.3
25	299	337	24.5	220	±	171	77.4
26	320	570	77.5	323	±	246	76.4
27	238	371	72.4	227	±	150	65.9
30	126	127	88.4	114	±	22.0	19.3
36	29.3	40.2	21.3	30.3	±	9.49	31.3
37	48.2	58.2	44.6	50.3	±	7.05	14.0
38	278	194	62.1	178	±	109	61.1
39	166	300	83.9	183	±	109	59.5
42	85.7	63.9	161	104	±	50.9	49.2
48	23.2	27.1	70.8	40.4	±	26.4	65.5
PK Parameters
Rsq_adj	1.00	0.820	−0.715	—	±	—	—
No. points used for T1/2	3.00	4.00	3.00	ND	±	—	—
Cmax (ng/mL)	320	570	273	388	±	160	41.2
Tmax (h)	0.500	26.0	0.500	9.00	±	14.7	164
T1/2 (h)	3.17	3.06	19.4	8.54	±	9.40	110
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12 (ng · h/mL)	417	718	566	567	±	151	26.6
AUC0-24 (ng · h/mL)	1429	1980	1221	1543	±	393	25.4
AUC0-36 (ng · h/mL)	3035	4210	1882	3042	±	1164	38.3
AUC24-48 (ng · h/mL)	2644	3350	1832	2609	±	760	29.1
AUC0-last (ng · h/mL)	4073	5330	3053	4152	±	1141	27.5
AUC0-inf (ng · h/mL)	4179	5450	5034	4888	±	648	13.3
MRT0-last (h)	25.8	24.3	27.0	25.7	±	1.35	5.26
MRT0-inf (h)	26.5	24.9	46.3	32.6	±	11.9	36.6
AUCExtra (%)	2.54	2.19	39.4	14.7	±	21.4	145
AUMCExtra (%)	5.04	4.62	64.6	24.8	±	34.5	139

Table 8 lists pharmacokinetic data of MRTA197 formulation. FIG. 7 is a graph of plasma concentration of MRTX1133 after MRTA197 dosing.

TABLE 8
Summary of MRTA197 Pharmacokinetic Parameters
MRTA197

	D3001	D3002	D3003	Mean		SD	CV (%)

Time (h)
0	BQL	BQL	BQL	ND	±	ND	ND
0.25	51.3	144	90.3	95.2	±	46.5	48.9
0.5	119	787	221	376	±	360	95.8
1	134	357	370	287	±	133	46.2
2	138	247	214	200	±	55.9	28.0
4	18.5	109	181	103	±	81.4	79.2
8	8.58	31.4	119	53.0	±	58.3	110
12	5.65	16.3	69.9	30.6	±	34.4	112
13	66.9	169	105	114	±	51.6	45.4
14	185	571	581	446	±	226	50.7
15	431	624	539	531	±	96.7	18.2
18	125	174	199	166	±	37.6	22.7
24	31.4	156	123	103	±	64.6	62.4
25	547	602	536	562	±	35.4	6.30
26	436	516	328	427	±	94.3	22.1
27	330	435	244	336	±	95.7	28.4
30	231	324	261	272	±	47.5	17.5
36	59.6	117	137	105	±	40.2	38.4
37	213	263	439	305	±	119	38.9
38	291	733	430	485	±	226	46.6
39	199	339	286	275	±	70.7	25.7
42	61.8	148	334	181	±	139	76.7
48	31.9	68.1	90.9	63.6	±	29.8	46.8
PK Parameters
Rsq_adj	0.867	0.914	0.847	—	±	—	—
No. points used for T1/2	5.00	3.00	5.00	ND	±	—	—
Cmax (ng/mL)	547	787	581	638	±	130	20.3
Tmax (h)	25.0	0.500	14.0	13.2	±	12.3	93.2
T1/2 (h)	3.43	4.05	5.04	4.17	±	0.812	19.5
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12 (ng · h/mL)	466	1384	1863	1238	±	710	57.3
AUC0-24 (ng · h/mL)	2240	4423	4824	3829	±	1391	36.3
AUC0-36 (ng · h/mL)	4990	8135	7724	6950	±	1709	24.6
AUC24-48 (ng · h/mL)	3987	6171	5995	5384	±	1214	22.5
AUC0-last (ng · h/mL)	6226	10594	10820	9213	±	2590	28.1
AUC0-inf (ng · h/mL)	6384	10991	11481	9619	±	2812	29.2
MRT0-last (h)	25.3	24.7	25.0	25.0	±	0.300	1.20
MRT0-inf (h)	26.0	25.7	26.7	26.1	±	0.513	1.96
AUCExtra (%)	2.48	3.62	5.76	3.95	±	1.67	42.1
AUMCExtra (%)	5.05	7.57	11.9	8.17	±	3.46	42.4

Table 9 lists pharmacokinetic data of MRT-A13-2 formulation. FIG. 8 is a graph of plasma concentration of MRTX1133 after MRT-A13-2 dosing. Capsule dosing was carried out on 3 Beagle dogs (N=3): 70 mg/capsule, 4 capsules/animal, 280 mg/animal/dose, twice a day (BID) for 2 days.

TABLE 9
Summary of MRT-A13-2 Pharmacokinetic Parameters
Plasma concentration (ng/mL)

	D1001	D1002	D1003	Mean		SD	CV (%)

Time (h)
0.00	BQL	BQL	BQL	ND	±	ND	ND
0.250	177	BQL	BQL	ND	±	ND	ND
0.500	593	1.89	2.25	199	±	341	171
1.00	243	16.4	25.1	94.8	±	128	135
2.00	62.3	290	18.9	124	±	146	118
4.00	39.1	138	47.0	74.7	±	55.0	73.6
8.00	11.6	21.8	13.8	15.7	±	5.37	34.1
12.0	8.01	14.5	7.65	10.1	±	3.86	38.3
13.0	501	118	474	364	±	214	58.7
14.0	729	476	828	678	±	182	26.8
15.0	260	598	298	385	±	185	48.0
18.0	99.7	190	74.9	122	±	60.6	49.8
24.0	39.9	62.5	41.7	48.0	±	12.6	26.2
25.0	188	146	69.8	135	±	59.9	44.5
26.0	261	356	265	294	±	53.7	18.3
27.0	248	484	418	383	±	122	31.8
30.0	250	128	80.2	153	±	87.6	57.3
36.0	121	73.7	38.3	77.7	±	41.5	53.4
37.0	203	46.3	118	122	±	78.4	64.1
38.0	458	291	87.5	279	±	186	66.5
39.0	346	490	381	406	±	75.1	18.5
42.0	172	217	167	185	±	27.5	14.9
48.0	59.7	68.0	63.7	63.8	±	4.15	6.51
PK Parameters
Rsq_adj	0.989	0.984	0.958	—	±	—	—
No. points used for T1/2	3.00	3.00	3.00	3.00	±	—	—
Cmax (ng/mL)	729	598	828	718	±	115	16.1
Tmax (h)	14.0	15.0	14.0	14.3	±	0.577	4.03
T1/2 (h)	3.60	3.21	3.59	3.47	±	0.222	6.41
Tlast (h)	48.0	48.0	48.0	48.0	±	—	—
AUC0-12 (ng · h/mL)	722	978	260	653	±	364	55.7
AUC0-24 (ng · h/mL)	2940	3634	2495	3023	±	574	19.0
AUC0-36 (ng · h/mL)	5326	5778	3986	5030	±	932	18.5
AUC0-last (ng · h/mL)	7581	8128	5779	7163	±	1229	17.2
AUC0-inf (ng · h/mL)	7891	8443	6109	7481	±	1220	16.3
MRT0-last (h)	26.1	25.3	26.3	25.9	±	0.529	2.04
MRT0-inf (h)	27.2	26.3	27.8	27.1	±	0.755	2.79
AUCExtra (%)	3.93	3.73	5.39	4.35	±	0.906	20.8
AUMCExtra (%)	7.68	7.46	10.3	8.48	±	1.58	18.6

Example 3: Pharmacokinetics in Humans

The pharmacokinetics [PK] of the MRTX1133 formulation after oral administration has been evaluated in 25 subjects across 3 escalating dose frequencies under fasting conditions (200 mg twice daily [BID], 400 mg BID, and 800 mg BID), as well as evaluation of 400 mg BID when administered with a low-fat meal (i.e., under fed conditions). The mean (+standard deviation) single-dose and multiple-dose pharmacokinetic profiles of the evaluated doses are presented in FIG. 9 and FIG. 10, respectively. Individual single- and multiple-dose PK profiles can be found in FIG. 11. For all figures, the X-axis represents nominal time of sample collection (hours [h]) and the Y-axis represents plasma concentration (ng/mL). Table 10 lists PK data following the oral administration of a single dose and multiple doses of MRTX1133 formulation by dose level and subject.

When the MRTX1133 dose was increased from 200 mg BID to 400 mg BID under fasted conditions, it resulted in an increase in the mean exposure, approximately 1.8-fold following a single dose and 4.4-fold following multiple doses. However, the mean single- and multiple-dose exposure did not change in a clinically meaningful manner when the dose was increased from 400 mg BID to 800 mg BID under fasted conditions, when accounting for the high degree of inter-patient variability.

The administration of a low-fat meal with 400 mg BID did not result in a clinically meaningful change in exposure compared to administration under fasted conditions.

Overall, the MRTX1133 formulation exhibited very high inter-patient variability across all dose levels, with the % CV ranging from approximately 65 to 200%. A select number of patients receiving MRTX1133 formulation (200 mg BID fasted: 0/5, 400 mg BID fasted: 3/7, 400 mg BID fed: 1/5, 800 mg BID fasted: 3/8) were able to achieve the target human efficacious exposure derived from mouse xenograft models (>40 to 60 ng/mL for ≥8 h of a 12 h dosing interval), following administration of multiple oral doses.

TABLE 10
Summary of MRTX1133 Clinical Pharmacokinetic Parameters
Single oral dose of 200 mg under fasted conditions

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5				CV
Time (h)	(301-002)	(301-003)	(304-002)	(304-004)	(313-002)	Mean		SD	(%)
0	BQL	BQL	BQL	BQL	BQL	NC	±	NC	NC
0.5	12.0	7.61	8.20	27.8	BQL	11.1	±	10.3	92.5
1	116	6.88	44.6	44.6	9.39	44.3	±	44.0	99.4
1.5	49.8	3.38	57.9	41.4	42.7	39.0	±	21.0	5..8
2	20.4	4.01	26.7	23.5	122	39.3	±	47.0	120
4	7.45	21.0	4.79	4.8	114	30.4	±	47.2	155
6	3.04	8.00	1.60	1.82	44.8	11.9	±	18.6	157
8	2.37	4.77	0.954	1.22	23.6	6.58	±	9.63	146
12	1.73	2.86	0.678	0.912	16.0	4.44	±	6.52	147
24	0.521	ND	1.08a	ND	ND	0.521	±	NC	NC
48	BQL	ND	ND	ND	ND	NC	±	NC	NC
72	BQL	ND	ND	ND	ND	NC	±	NC	NC
96	BQL	ND	ND	ND	ND	NC	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Geo			Geo CV
PK Parameters	(301-002)	(301-003)	(304-002)	(304-004)	(313-002)	Mean		SD	(%)
Rsq_adj	NC	NC	NC	NC	NC	NC	±	NC	NC
No. points used for T1/2	NC	NC	NC	NC	NC	NC	±	NC	NC
Cmax (ng/mL)	116	21.0	57.9	44.6	122	59.8	±	44.7	83.8
Tmax (h)b	1.0	4.0	1.5	1.0	2.0	1.5	±	1.0-4.0	NC
T1/2 (h)	NC	NC	NC	NC	NC	NC	±	NC	NC
Tlast (h)	24	12	12a	12	12	NC	±	NC	NC
AUC0-12 (ng · h/mL)	140	89.2	98.1	99.3	585	148	±	215	92.6
AUC0-last (ng · h/mL)	152	89.2	98.1	99.3	585	151	±	214	92.5
AUC0-infc (ng · h/mL)	157	107	103	107	653	165	±	240	92.9
AUCExtrap (%)	3.42	16.3	4.88	7.77	10.4	7.4	±	5.1	67.6

Multiple oral doses of 200 mg BID under fasted conditions

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5				CV
Time (h)	(301-002)	(301-003)	(304-002)	(304-004)	(313-002)	Mean		SD	(%)
0	1.63	5.45	0.632	2.26	16.7	5.33	±	6.60	124
0.5	57.5	5.15	49.4	13.1	15.3	28.1	±	23.6	84.1
1	85.0	12.6	8.00	34.7	15.2	31.1	±	31.8	102
1.5	55.0	15.0	4.08	56.2	17.1	33.1	±	26.5	80.2
2	29.9	7.52	4.43	35.7	15.6	20.1	±	12.6	62.4
4	12.3	5.95	1.64	5.01	ND	6.62	±	4.49	67.8
6	5.03	4.63	1.14	3.28	ND	3.85	±	2.12	55.0
8	3.22	4.13	0.878	2.44	ND	2.79	±	1.57	56.1
12	2.72	5.45	0.928	2.08	ND	2.46	±	1.33	54.2
24	ND	ND	0.730a	ND	ND	NC	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Geo			Geo CV
PK Parameters	(301-002)	(301-003)	(304-002)	(304-004)	(313-002)	Mean		SD	(%)
Cmax (ng/mL)	85.0	15.0	49.4	56.2	17.1	36.0	±	29.2	89.6
Tmax (h)b	1.0	2.0	0.5	1.5	1.5	1.5	±	0.5-2.0	NC
Tlast (h)	12	12	12	12	2.0	NC	±	NC	NC
AUC0-12 (ng · h/mL)	181	84.0	42.9	115	NC	93.1	±	58.4	66.6
AUC0-last (ng · h/mL)	181	84.0	42.9	115	31.9	75.2	±	60.4	81.1
Cmax Accumulation Ratio	0.73	0.71	0.85	1.26	0.14	0.6	±	0.4	102
AUC0-12 Accumulation Ratio	1.30	0.94	0.44	1.16	NC	0.9	±	0.4	52.1
Peak to Trough Ratio	52.1	2.75	78.2	24.9	1.02	12.3	±	33.2	598

Single oral dose of 400 mg under fasted conditions

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7				CV
Time (h)	(301-004)	(301-007)	(304-005)	(304-008)	(305-003)	(313-003)	(313-005)	Mean		SD	(%)
0	BQL	BQL	BQL	BQL	BQL	BQL	BQL	NC	±	NC	NC
0.5	BQL	51.4	66.3	71	15.2	51.5	43.7	42.7	±	26.1	61.1
1	39.5	62	39.8	38.2	15.2	71.7	99.1	52.2	±	27.6	52.8
1.5	57.4	9.42	22.3	49.5	7.59	69.1	127	48.9	±	41.9	85.8
2	62.1	11	17.6	30.8	5.83	268	188	83.3	±	103	124
4	54.3	6.83	9.91	7.09	37	281	54.8	64.4	±	97.8	152
6	39.9	2.9	4.98	5.22	6.99	158	23.8	34.5	±	56.1	162
8	23	0.923	3.27	3.59	2.91	106	21.2	23.0	±	37.7	164
12	15.1	1.05	2.16	2.43	1.79	49.2	11.4	11.9	±	17.4	146
24	3.75	ND	ND	ND	ND	ND	ND	3.75	±	NC	NC
48	1.46	ND	ND	ND	ND	ND	ND	1.46	±	NC	NC
72	0.872	ND	ND	ND	ND	ND	ND	0.872	±	NC	NC
96	0.538	ND	ND	ND	ND	ND	ND	0.538	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7	Geo			Geo CV
PK Parameters	(301-004)	(301-007)	(304-005)	(304-008)	(305-003)	(313-003)	(313-005)	Mean		SD	(%)
Rsq_adj	0.999	NC	NC	NC	NC	NC	NC	NC	±	NC	NC
No. points used for T1/2	3	NC	NC	NC	NC	NC	NC	NC	±	NC	NC
Cmax (ng/mL)	62.1	62.0	66.3	71.0	37.0	281	188	86.2	±	90.1	82.2
Tmax (h)b	2.0	1.0	0.5	0.5	4.0	4.0	2.0	2.0	±	0.5-4.0	NC
T1/2 (h)	33.3	NC	NC	NC	NC	NC	NC	33.3	±	NC	NC
Tlast (h)	96	12	12	12	12	12	12	NC	±	NC	NC
AUC0-12 (ng · h/mL)	410	94.3	128	151	118	1,696	580	263	±	578	146
AUC0-last (ng · h/mL)	610	94.3	128	151	118	1,696	580	278	±	580	155
AUC0-infc (ng · h/mL)	636	98.4	137	169	126	1,950	670	304	±	668	161
AUCExtrap (%)	4.07	4.18	6.90	10.7	6.70	13.0	13.4	7.6	±	3.9	53.3

Multiple oral doses of 400 mg BID under fasted conditions

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7				CV
Time (h)	(301-004)	(301-007)	(304-005)	(304-008)	(305-003)	(313-003)	(313-005)	Mean		SD	(%)
0	57.3	0.579	33.1	9.12	4.7	9.83	21.3	19.4	±	20.0	103
0.5	79.1	58.5	82.8	83.0	29.7	23.6	152	72.7	±	42.8	58.9
1	129	31.5	61.2	38.4	11.5	44.7	285	85.9	±	95.4	111
1.5	90.2	28.5	38.9	32.3	15.2	38.0	209	64.6	±	67.9	105
2	99.0	27.2	55.6	23.4	21.1	30.0	83.1	48.5	±	31.6	65.1
4	82.8	11.0	115	23.8	5.34	233	70.5	77.3	±	79.8	103
6	189	2.51	45.3	10.7	4.38	148	43.8	63.4	±	74.8	118
8	88.9	2.27	33.3	8.36	3.68	110	35.5	40.3	±	43.0	107
12	76.9	2.76	31.2	6.42	3.71	42.1	31.3	27.8	±	26.8	96.4
24	ND	ND	ND	ND	ND	ND	ND	NC	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7	Geo			Geo CV
PK Parameters	(301-004)	(301-007)	(304-005)	(304-008)	(305-003)	(313-003)	(313-005)	Mean		SD	(%)
Cmax (ng/mL)	189	58.5	115	83.0	29.7	233	285	111	±	95.5	96.6
Tmax (h)b	6.0	0.5	4.0	0.5	0.5	4.0	1.0	1.0	±	0.5-6.0	NC
Tlast (h)	12	12	12	12	12	12	12	NC	±	NC	NC
AUC0-12 (ng · h/mL)	1,237	128	640	211	89.4	1,239	821	410	±	499	153
AUC0-last (ng · h/mL)	1,237	128	640	211	89.4	1,239	821	410	±	499	153
Cmax Accumulation Ratio	3.04	0.94	1.73	1.17	0.80	0.83	1.52	1.3	±	0.8	50.8
AUC0-12 Accumulation Ratio	3.02	1.35	5.02	1.40	0.76	0.73	1.41	1.6	±	1.5	79.4
Peak to Trough Ratio	3.30	101	3.47	9.10	6.32	23.7	13.4	11.1	±	35.2	180

Single oral dose of 400 mg with a low-fat meal

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5				CV
Time (h)	(303-006)	(310-004)	(311-003)	(314-005)	(314-006)	Mean		SD	(%)
0	BQL	BQL	BQL	BQL	BQL	NC	±	NC	NC
1	77.0	18.7	28.2	85.1	24.7	46.7	±	31.6	67.7
2	83.2	39.9	6.47	76.4	12.0	43.6	±	35.5	81.4
3	71.5	ND	3.84	85.8	13.6	43.7	±	41.0	93.8
4	65.9	93.9	2.43	99.8	36.5	59.7	±	40.7	68.2
5	41.4	41.4	1.41	163	22.5	53.9	±	63.2	117
6	59.5	16.9	1.02	125	15.5	43.6	±	50.5	116
8	36.2	6.62	0.538	48.8	9.72	20.4	±	20.9	103
12	17.5	3.17	BQL	30.4	5.32	11.3	±	12.6	112
24	ND	ND	ND	7.59	ND	7.59	±	NC	NC
48	ND	ND	ND	3.13	ND	3.13	±	NC	NC
72	ND	ND	ND	2.13	ND	2.13	±	NC	NC
96	ND	ND	ND	1.12	ND	1.12	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Geo			Geo CV
PK Parameters	(303-006)	(310-004	(311-003)	(314-005)	(314-006)	Mean		SD	(%)
Rsq_adj	NC	NC	NC	0.966	NC	NC	±	NC	NC
No. points used for T1/2	NC	NC	NC	4	NC	NC	±	NC	NC
Cmax (ng/mL)	83.2	93.9	28.2	163	36.5	66.6	±	54.0	82.3
Tmax (h)b	2.0	4.0	1.0	5.0	4.0	4.0	±	1.0	5.0
T1/2 (h)	NC	NC	NC	27.2	NC	27.2	±	NC	NC
Tlast (h)	12	12	8	96	12	NC	±	NC	NC
AUC0-12 (ng · h/mL)	564	305	42.6	889	169	256	±	338	174
AUC0-last (ng · h/mL)	564	305	42.6	1,307	169	277	±	503	207
AUC0-infc (ng · h/mL)	651	317	43.2	1,351	200	300	±	519	211
AUCExtrap (%)	13.4	3.77	3.88	3.25	15.3	6.3	±	5.9	87.8

Multiple oral doses of 400 mg BID with a low-fat meal

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5				CV
Time (h)	(303-006)	(310-004)	(311-003)	(314-005)	(314-006)	Mean		SD	(%)
0	53.8	2.95	4.53	ND	5.39	16.7	±	24.8	149
1	390	90.3	48.2	ND	23.0	138	±	170	124
2	203	27.3	17.9	ND	18.5	66.7	±	91.0	136
3	170	24.8	9.11	ND	16.6	55.1	±	76.8	139
4	129	250	6.60	ND	14.7	100	±	115	114
5	106	39.4	5.09	ND	8.57	39.8	±	46.8	118
6	89.4	18.8	4.07	ND	7.64	30.0	±	40.1	134
8	73.2	8.47	3.12	NI	7.05	23.0	±	33.6	146
12	55.3	5.28	2.90	ND	5.71	17.3	±	25.4	147
24	ND	ND	ND	ND	ND	NC	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Geo			Geo CV
PK Parameters	(303-006)	(310-004)	(311-003)	(314-005)	(314-006)	Mean		SD	(%)
Cmax (ng/mL)	390	250	48.2	NC	23.0	102	±	174	224
Tmax (h)b	1.0	4.0	1.0	NC	1.0	1.0	±	1.0-4.0	NC
Tlast (h)	12	12	12	NC	12	NC	±	NC	NC
AUC0-12 (ng · h/mL)	1,475	457	107	NC	127	310	±	642	187
AUC0-last (ng · h/mL)	1,475	457	107	NC	127	310	±	642	187
Cmax Accumulation Ratio	4.69	2.66	1.71	NC	0.63	1.9	±	1.7	103
AUC0-12 Accumulation Ratio	2.61	1.50	2.52	NC	0.75	1.7	±	0.9	63.4
Peak to Trough Ratio	7.25	84.7	10.6	NC	4.27	12.9	±	38.8	213

Single oral dose of 800 mg under fasted conditions

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7	Subject 8				CV
Time (h)	(301-006)	(304-007)	(305-004)	(305-005)	(307-004)	(309-003)	(312-003)	(313-004)	Mean		SD	(%)
0	BQL	BQL	0	BQL	BQL	BQL	BQL	BQL	NC	±	NC	NC
0.5	77.9	1530	101	55.3	14.9	13.1	78.5	11.2	235	±	524	223
1	129	1760	79.9	64.3	23.4	11.4	205	15.4	286	±	599	209
1.5	108	489	74.2	48.9	13.8	24	437	16.2	151	±	195	129
2	78.2	328	29.3	27.7	11.2	80.5	374	8.36	117	±	147	126
4	14.7	108	6.77	8.95	24	69.2	302	6.89	67.6	±	101	150
6	4.95	37.3	3.2	8.44	8.62	62.5	329	8.79	57.9	±	111	193
8	2.73	26	1.12	4.28	10.1	53.2	266	33.8	49.7	±	89.3	180
12	2.06	14.4	1.22	2.51	2.1	22.3	ND	43.3	12.6	±	15.8	126
24	0.894	ND	ND	ND	ND	ND	50.2	ND	25.5	±	34.9	136
48	BQL	ND	ND	ND	ND	ND	ND	ND	NC	±	NC	NC
72	BQL	ND	ND	ND	ND	ND	ND	ND	NC	±	NC	NC
96	BQL	ND	ND	ND	ND	ND	ND	ND	NC	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7	Subject 8	Geo			Geo CV
PK Parameters	(301-006)	(304-007)	(305-004)	(305-005)	(307-004)	(309-003)	(312-003)	(313-004)	Mean		SD	(%)
Rsq_adj	NC	NC	NC	NC	NC	NC	NC	NC	NC	±	NC	NC
No. points	NC	NC	NC	NC	NC	NC	NC	NC	NC	±	NC	NC
used for T1/2
Cmax (ng/mL)	129	1,760	101	64.3	24.0	80.5	437	43.3	123	±	593	234
Tmax (h)b	1.0	1.0	0.5	1.0	4.0	2.0	1.5	12	1.2	±	0.5-12	NC
T1/2 (h)	NC	NC	NC	NC	NC	NC	NC	NC	NC	±	NC	NC
Tlast (h)	24	12	12	12	12	12	24	12	NC	±	NC	NC
AUC0-12	287	2,573	182	167	133	583	3,221	251	440	±	1,237	192
(ng · h/mL)
AUC0-last	315	2,573	182	167	133	583	4,421	251	463	±	1,579	215
(ng · h/mL)
AUC0-infc	317	2,665	185	181	141	708	4,902	NC	543	±	1,826	251
(ng · h/mL)
AUCExtrap (%)	4.05	3.44	1.58	8.08	5.77	17.7	9.81	NC	5.6	±	5.4	92.6

Multiple oral doses of 800 mg BID under fasted conditions

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7	Subject 8				CV
Time (h)	(301-006)	(304-007)	(305-004)	(305-005)	(307-004)	(309-003)	(312-003)	(313-004)	Mean		SD	(%)
0	2.55	19.3	2.01	12	10.6	36.5	78.1	3.63	20.6	±	25.9	126
0.5	7.77	241	34.4	131	11.2	38.8	241	72.6	97.2	±	97.0	99.8
1	9.9	149	25.9	136	12.9	47.4	670	44.1	137	±	222	162
1.5	10.7	80.9	24.5	143	23.5	45.1	483	44.3	107	±	158	148
2	8.1	84.2	30.8	165	29.8	83.3	531	41	122	±	173	142
4	19.9	26.3	13.4	67.4	22.5	105	812	35.9	138	±	274	199
6	38.2	18.9	4.94	51.2	26.1	89.7	609	14.1	107	±	205	192
8	22.7	18.1	3.5	30.1	21.6	57	288	8.66	56.2	±	95.0	169
12	11.1	16.8	2.59	12.1	12.4	42.7	ND	5.14	14.7	±	13.2	90.1
24	ND	ND	ND	ND	ND	ND	ND	ND	NC	±	NC	NC

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Subject 6	Subject 7	Subject 8	Geo			Geo CV
PK Parameters	(301-006)	(304-007)	(305-004)	(305-005)	(307-004)	(309-003)	(312-003)	(313-004)	Mean		SD	(%)
Cmax (ng/mL)	38.2	241	34.4	165	29.8	105	812	72.6	99.5	±	263	163
Tmax (h)b	6.0	0.5	0.5	2.0	2.0	4.0	4.0	0.5	2.0	±	0.5-6.0	NC
Tlast (h)	12	12	12	12	12	12	8	12	NC	±	NC	NC
AUC0-12	227	509	130	744	248	820	NC	264	347	±	273	77.2
(ng · h/mL)
AUC0-last	227	509	130	744	248	820	4,458	264	477	±	1,450	130
(ng · h/mL)
Cmax	0.30	0.14	0.34	2.57	1.24	1.30	1.86	1.68	0.8	±	0.9	144
Accumulation
Ratio
AUC0-12	0.79	0.20	0.71	4.46	1.87	1.41	NC	1.05	1.0	±	0.9	123
Accumulation
Ratio
Peak to	15.0	12.5	17.1	13.8	2.81	2.88	10.4	20.0	9.6	±	6.2	91.2
Trough Ratio
aSample taken after PM dose. Concentration excluded from analysis and summary statistics.
bMedian and Min-Max presented rather than Mean and SD.
cAUCinf not reported and excluded from summary statistics if % AUC extrapolated >20%.
dExcluded from summary statistics due to incomplete PK sampling.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of the specification that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.